Preclinical and Clinical Applications

This section contains examples applying the presented concepts in which measured Cb and /U/b, satellite rat neuropharmacokinetic studies, and/or measured Cp and fU/P were used to determine compound-dependent Cb,u required for a specific mechanism-mediated in vivo effect. The presented studies demonstrate the utility of Cb,u in defining target pharmacology relationships for small molecules affecting transmembrane proteins. 

---

In addition to screening for new therapeutic targets for lead candidate selection, pharmacogeneomics and pharmacoproteomics have a number of other preclinical and clinical applications. 

Current clinical and preclinical biomarkers suffer from lack of target organ specificity, sensitivity issues, and poor mechanistic insight. There is therefore a lot of interest in the field of biomarker discovery to overcome these issues, for both clinical and preclinical applications. In this chapter we set out to demonstrate how in vitro techniques are an indispensable tool in the development and discovery of novel mechanistically based biomarkers. We provide examples of several novel biomarkers which have been either discovered in vitro or where such systems have been used to elucidate key mechanistic information. Many of these biomarkers are more than innocent bystanders leaked into the surrounding tissue, with most highly implicated in cell and tissue survival as well as tissue differentiation. These new biomarkers will be not only useful for current preclinical and clinical applications but also advantageous in the development of better in vitro systems in order to reduce or replace animal testing. 

Napp, J., Mathejczyk, J.E., Alves, F. Optical imaging in vivo with a focus on paediatric disease technical progress, current preclinical and clinical applications and future perspectives. Pediatric Radiology 41(2), 161-175 (2011)... 

The area of racemic switches where a single enantiomer is developed subsequently to a corresponding racemate which is already on the market has attracted much interest [7, 8]. A description of the preclinical and clinical development of dexketoprofen provides a detailed example of one of these racemic switches [21]. The regulations in Europe and the US both allow for the development of a single enantiomer from a racemate by the use of bridging studies between the old and new applications. One problem to be considered is how a company which was not responsible for the original development can provide equivalent data. 

An application for a marketing authorisation must be accompanied, among other items, by specified pharmaceutical, preclinical and clinical particulars and documents (the dossier ). Three important summary documents in the dossier are the SPC, a Package or Patient Information Leaflet (PIL), and the sales presentation of the product (label). The SPC has a formally prescribed structure (Box 17.1), and forms the basis for authorised chnical prescribing of the medicinal product concerned. 

The data exclusivity arrangements are primarily of interest to sponsors of products that are not otherwise protected by patent. A sponsor of a generic product may avoid the need for TG A to refer to protected information by submitting a full Category 1 application for registration, including preclinical and clinical data, although this would be unusual. 

There are two levels of evaluation of applications for clinical trials of medicines under the CTX scheme. A 30 working day period for evaluation of a CTX application applies when the supporting data relate only to chemical, pharmaceutical and biological issues. A 50 working day period applies for applications supported by chemical, pharmaceutical and biological, preclinical and clinical data. These evaluation times commence from the date of acceptance of the apphcation or receipt of the appropriate fee. The fee for a 30 day CTX application is currently AUD 1240 and for a 50 day application AUD 15300. 

Figure 4.17. Progression of a new molecular entity through preclinical and clinical evaluation for safety and efficacy. Preclinical and clinical study results are reviewed by FDA through several pathways, including traditional and nontraditional pathways. A majority of submitted new drug applications are approved for human use. Additional details on nontraditional clinical pathways are presented in Box 4.7. (Figure adapted from an FDA report, 1999)...

Fig. 1. The Pharmaceutical Pipeline. The different phases of drug development are outlined, starting with a lead compound and moving forward through preclinical and clinical testing towards market approval. (CS candidate selection IND investigational new drug application POC proof of concept NDA new drug application FTIH first time in human).

Class III Premarket Approval. Similar to a new drug approval, a premarket approval grants the applicant a license to market a specific well-characterized device. These devices are subject to the requirements of Section 515 of the Food, Drug, and Cosmetic Act. A post-amendment device is a device put in commercial distribution after May 28, 1976. If it is not substantially equivalent to a preamendment device it is automatically in Class III, and a premarket approval application (PMA) is required. The application must include reports of preclinical and clinical studies done in support of claims of safety and efficacy as well as any labeling claims made for the device. Once the PMA is submitted, the FDA determines whether the application includes the required information. If the PMA is suitable for scientific review, the FDA has 180 days from the filing date to approve or deny the application. Polybutester, polydioxanone, polyglyconate, and ePTFE sutures are all regulated as Class III devices. 

Fig. 1.4 Examples of the application of pharmacokinetic/pharmacodynamic (PK/PD) concepts in preclinical and clinical drug development (from [10]).

This textbook provides a comprehensive overview on the PK and PD of biotech-derived drag products, highlights the specific requirements and challenges related to PK and PK/PD evaluations of these compounds and provides examples of their application in preclinical and clinical drag development The impetus for this project originated from the notion that at the time of its initiation there was no comprehensive publication on the market that specifically addressed this topic. 

---